THe presence of hypoxic cells in tumors has been considered as one of the main limiting factors for control of human tumors by radiotherapy. Although a number of approaches have been proposed to overcome the hypoxic protection in radiotherapy, none of them are yet clinically useful. Our studies demonstrated that 5-thio-D-glucose is specifically cytotoxic toward hypoxic cells in vitro. Furthermore, it sensitizes hypoxic cells to X-irradiation while it protects oxic cells from radiation damage. It was also observed that this compound is able to diffuse into the inner part of multicell spheroids with a diameter of 1000 mu and kills the chronically hypoxic cells. We also found that the cytotoxicity of this compound toward hypoxic cells can be dramatically enhanced by mild hyperthermia at 40-43 degrees C. We are now working on the effect of 5-thio-D-glucose on 3 animal tumor models in vivo. The dose of drug, mode of administration, sequence of drug administration and C X-irradiation, and also the possibility of combining 5-thio-D-glucose with hyperthermia and radiotherapy are being investigated.